placebo and nocebo effects

A recent summary article reviewed both placebo and nocebo effects, reflecting respectively increases in beneficial or harmful results (see placebo nocebo review nejm2020 in dropbox, or DOI: 10.1056/NEJMra1907805). These placebo/nocebo effects occur in clinical trials (specifically comparing an active agent with placebo), informing patients about medical treatments, and public health campaigns

Details:

-- placebo effects can be associated with the release of various hormones including endogenous opioids, endocannabinoids, dopamine, oxytocin, and vasopressin.

    -- these effects seem to be specific: for example the placebo effect in patients with Parkinson’s disease seems to be specific to dopamine release, though dopamine release is not associated with placebo effects on acute or chronic pain

    -- patients subjected to experimental pain had benefit from the potent opioid remifentanil; but those patients who thought incorrectly that the remifentanil had been stopped had the beneficial pain affects blocked (of note, studies of their brain showed hippocampal activation, suggesting a role for stress and memory in this nocebo effect)

        -- nocebo effects in experimentally produce pain seem to be mediated by the neuropeptide cholecystokinin and blocked by its antagonist proglumide

    -- nocebo effects are also well documented when clinicians discuss side effects: for example, 31% of patients who were informed of the potential sexual side effects of atenolol had these adverse sexual effects, whereas 16% of those not so informed had them

-- one common situation that seems to accentuate placebo effects is in groups: for example the placebo effect of patient’s expectations for a medication effect is enhanced by observing benefit in another person; similarly for negative nocebo effects

   -- another example of the effect of expectations is that experimentally-induced low-intensity pain in patients is perceived as high-intensity pain by just a verbal suggestion that it is high-intensity

   -- and patients' expectations can be driven by reports in the mass media and lay press: studies have shown for example that the perceived adverse effects of statins are associated with the intensity of negative media coverage of these adverse effects

-- there also seem to be genetic influences on the placebo and nocebo effects: these effects have been associated with SNPs in the dopamine, opioid, and endocannabinoid genes (also, see http://gmodestmedblogs.blogspot.com/2015/04/placebo-genetics-and-placebome.html , which reviews several studies including some showing that there is a more profound placebo response to those with genetic polymorphisms associated with increased opioid and dopamine receptor activation and higher levels of these chemicals)

-- suggestions as to how clinicians can minimize the nocebo effects of medications or procedures, given the need to discuss openly the positive and negative potential outcomes:

    -- explore the patient’s expectations of the benefit of the treatment, on a visual analog scale (for example a study of elective cardiac surgery found that understanding patients fears and expectations reduced disability outcome 6 months later; another study in patients undergoing intra-abdominal surgery found a 50% reduction in postoperative pain and narcotic use)

    -- the issue here is that many of patients' negative expectations are reinforced by mistaken beliefs, negative prior experiences, social messaging, worrisome information, etc. These potential nocebo effects can only be addressed effectively if the clinician is aware of the patients’ thoughts and concerns

    -- another approach is to educate the patient about the concept of “nocebo effects”, and asked the patient specifically if they want to hear about benign, nonspecific adverse effects of a treatment. It is useful to reassure the patient that these adverse effects are not harmful or medically dangerous.

-- and, having an empathic and trusting relationship between the clinician and the patient, with open communication, can palliate symptoms. objective studies have shown these clinician/patient relationships reduced levels of inflammation such as interleukin-8 and neutrophil counts in those with URIs.

    -- Other studies have also suggested that clinician communication involving good eye contact and not speaking in a monotone/not smiling also contribute to nocebo effects

-- another issue, elaborated in http://gmodestmedblogs.blogspot.com/2015/04/placebo-genetics-and-placebome.html , is the importance of having controlled trials with a no-treatment group. This has been done occasionally in studies as a means to quantify the placebo effect (e.g., a three-tiered study: active drug vs placebo vs no treatment), as noted in that blog

Commentary:

-- this article brings up one of my favorite studies: there was a set of studies on the effect of candesartan (an angiotensin receptor blocker) in different patient populations with heart failure (the CHARM studies), noting benefit for example in those with reduced ejection fraction. A subsequent analysis found that there was actually NO difference in response rate if one looks at those patients who actually had good adherence to taking the pills, independent of whether they were on the active medication or the placebo!! (see chf CHARM trial adherence lancet 2005 in dropbox, or DOI:10.1016/S0140-6736(05)67760-4). This suggests that those who really were engaged in treatment did better independent of the drug's specific effects. of course, those who adhered to the medicine may also be doing things that are more healthy overall than those not taking the meds...

-- the issue of enhanced expectations and enhanced placebo effect in groups is profound and reinforces several studies suggesting that group-based therapies, where patients learn from each other, are very effective in producing positive outcomes

-- another study finding benefits of placebo in patients with chronic low back pain found a significant placebo effect even when the patients were aware that they were taking placebo!!! (see http://gmodestmedblogs.blogspot.com/2016/11/benefits-of-placebo-for-low-back-pain.html).  maybe there is utility in having a "placebo pill" where the patient understands that it is a placebo???

So, it is evident that the placebo and nocebo effects can be quite profound, with several studies suggesting that placebo responses are on the order of 20 to 25%. It is also clear from the above that there may be some important variability in patients, some likely related to genetics (referred to as the placebome on the genome). But there are a few take-home messages:

-- the placebo and nocebo responses, not surprisingly, are associated with very real changes in hormones or their receptors in the patients

-- studies suggest that groups are helpful in augmenting the effects of interventions. There was an impressive talk I heard by an ED clinicians having group sessions post-ED visits finding improved clinical outcomes, even though all the patients had different clinical problems and different clinical interventions (i.e., just the reinforcement that a person was doing better after a successful ED visit seems to have other people have more successful outcomes)

-- it is likely to be clinically important to understand patients fears and expectations prior to starting a medication or other intervention, as a means to improve the likelihood of benefit and reduce the likelihood of feared harms

-- and, of course, a clinician who is empathic and has open communication with patients is likely to increase any placebo effects and decrease any nocebo effects

geoff​

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